Control of amino acid transport coordinates metabolic reprogramming in T-cell malignancy

• Published in: Leukemia 2017-12, Vol.31 (12), p.2771-2779
• Main Authors: Grzes, K M, Swamy, M, Hukelmann, J L, Emslie, E, Sinclair, L V, Cantrell, D A
• Format: Article
• Language: English
• Subjects: 13/31; 13/95; 631/67/2327; 631/67/70; 631/80/86; 631/92/577; 64/110; 692/4028/67/1990/291/1621/1916; 82/58; 82/80; 96/31; Acids; Acute lymphoblastic leukemia; Amino Acid Transport Systems - metabolism; Amino acids; Amino Acids - metabolism; Animal models; Animals; Biological Transport; c-Myc protein; Cancer Research; Cell proliferation; Chromosome 10; Chromosome deletion; Clonal deletion; Critical Care Medicine; Disease Models, Animal; Gene Expression; Genetic transformation; Glucose; Glucose metabolism; Glucose transport; Hematology; Homology; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Intensive; Internal Medicine; Leucine; Leukemia; Lymphatic leukemia; Lymphocytes; Lymphocytes T; Malignancy; Mass spectrometry; Mass spectroscopy; Mechanistic Target of Rapamycin Complex 1 - metabolism; Medicine; Medicine & Public Health; Metabolic Networks and Pathways; Metabolism; Mice; Mice, Knockout; Myc protein; Nutrients; Oncology; Original; original-article; Phosphatidylinositol; Phosphatidylinositol Phosphates - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - mortality; Proteomics; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; PTEN protein; Rapamycin; T cells; Tensin; TOR protein
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2017.160

This study explores the regulation and importance of System L amino acid transport in a murine model of T-cell acute lymphoblastic leukemia (T-ALL) caused by deletion of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). There has been a strong focus on glucose transport in leukemias but the present data show that primary T-ALL cells have increased transport of multiple nutrients. Specifically, increased leucine transport in T-ALL fuels mammalian target of rapamycin complex 1 (mTORC1) activity which then sustains expression of hypoxia inducible factor-1α (HIF1α) and c-Myc; drivers of glucose metabolism in T cells. A key finding is that PTEN deletion and phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P 3 ) accumulation is insufficient to initiate leucine uptake, mTORC1 activity, HIF1α or c-Myc expression in T cells and hence cannot drive T-ALL metabolic reprogramming. Instead, a key regulator for leucine transport in T-ALL is identified as NOTCH. Mass spectrometry based proteomics identifies SLC7A5 as the predominant amino acid transporter in primary PTEN −/− T-ALL cells. Importantly, expression of SLC7A5 is critical for the malignant transformation induced by PTEN deletion. These data reveal the importance of regulated amino acid transport for T-cell malignancies, highlighting how a single amino acid transporter can have a key role.